Crotanecine

One-pot synthesis of cyclic nitrones and their conversion to pyrrolizidines: 7a-epi-crotanecine inhibits alpha-mannosidases.[Pubmed:16468814]

J Org Chem. 2006 Feb 17;71(4):1614-9.

[reaction: see text] A new straightforward and inexpensive one-pot procedure is described for the preparation of enantiopure five-membered cyclic nitrones starting from the corresponding lactols. Its efficiency relies on the condensation of unprotected hydroxylamine with readily available lactols and on the chemoselectivity of the subsequent esterification with methanesulfonyl chloride. The targeted enantiomerically pure pyrroline N-oxides are versatile synthetic intermediates: one of the nitrones so-obtained has been converted into new polyhydroxypyrrolizidines, analogues of the alkaloids rosmarinecine and Crotanecine, which were assayed for their inhibitory activities toward 22 commercially available glycosidase enzymes. One of them ((-)-7a-epi-Crotanecine) is a potent and selective inhibitor of alpha-mannosidases from jack beans and almonds.

(2aS,3S,6S,7S,7bR)-7-[(dimethylphenyl)-silyl]-2-oxo-6-[(1R,2S)-2- phenylcyclo-hexyloxy]-2a,3,6,7,7a,7b-hexahydro-2H-1,4,5-trioxa-4a- azacyclopenta[cd]indene-3-carboxylic acid 1-methylethyl ester.[Pubmed:8900033]

Acta Crystallogr C. 1996 Oct 15;52 ( Pt 10):2558-61.

The structure of the title compound, C31H39NO7Si, was determined and found to be a fused tricyclic nitroso acetal. Remarkable features include a twist-boat conformation of the tetrahydro-1,2-oxazine ring and a highly pyramidalized N atom [Sigma (angles) = 310.6(6) degrees]. Three of the contiguous stereocenters in the nitroso acetal are of the same correct relative and absolute configuration as is found in (+)-Crotanecine.

Detection of sulphur-conjugated pyrrolic metabolites in blood and fresh or fixed liver tissue from rats given a variety of toxic pyrrolizidine alkaloids.[Pubmed:1412522]

Toxicol Lett. 1992 Oct;63(1):47-55.

Rats were given single injections of hepatotoxic pyrrolizidine alkaloids and killed after 30 h. Sulphur-bound pyrrolic metabolites from the alkaloids in samples of their blood or liver tissue were converted to extractable ethyl ethers of low molecular weight for detection and identification using TLC, HPLC or GC-MS. Liver samples were also preserved as an acetone-washed powder or in formalin-based fixative before being later subjected to similar analyses. S-Bound pyrrolic metabolites were identified in samples from rats given all the types of alkaloid tested, which included mono-esters (heliotrine, indicine), a diester (lasiocarpine), and macrocyclic diesters (retrorsine, senecionine). The pattern of pyrrolic metabolites from the Crotanecine-based alkaloid anacrotine differed and could be distinguished from retronecine- or heliotridine-based alkaloids. Whereas the alkaloids tested ranged widely in toxicity, single doses of 0.25 x acute LD50 or more led to detectable metabolites. Liver pyrroles remained detectable in fixed or powdered samples preserved for long periods. Similar tests on rats given monocrotaline continuously in their drinking water (20 mg/l) led to detectable pyrroles in blood after 12 days (total intake approx. 27 mg/kg) and in liver after 25 days. The metabolites remained detectable in rats killed 17 days after the alkaloid exposure was discontinued. The simple procedures described are applicable to the diagnosis of pyrrolizidine alkaloid exposure in livestock, using fresh or dried blood or fresh or preserved liver samples. They bring to pyrrolizidine toxicology for the first time the capability to demonstrate chemically that livestock (or people) have been exposed to these alkaloids many days or weeks previously.

Hepato- and pneumotoxicity of pyrrolizidine alkaloids and derivatives in relation to molecular structure.[Pubmed:1253333]

Chem Biol Interact. 1976 Mar;12(3-4):299-324.

62 pyrrolizidine alkaloids and derivatives have been screened for acute and chronic hepato- and pneumotoxicity by the single dose method previously described. This procedure is satisfactory for the compounds of medium to high hepatotoxicity but failed to detect toxicity in certain other compounds of known, low hepatotoxicity. New findings significant in relation to hepatotoxicity are as follows: (i) On a molar basis, diesters of heliotridine and retronecine are about 4 times as toxic as the respective mono-esters and heliotridine esters are 2-4 times as toxic as retronecine esters. (ii) Crotanecine esters are less toxic than retronecine esters, and the 6,9-diester madurensine, 2-4 times less toxic than the 7,9-diester anacrotine (the difference being ascribed to there being only one reactive alkylating centre in the toxic metabolite from madurensine). (iii) Hepatotoxicity was confirmed for 7-angelylheliotridine but not observed for 9-angelyheliotridine and 7- and 9-angelylretronecine. (iv) Other significant compounds failing to induce hepatotoxicity were 9-pivalyl- and 7,9-dipivalyheliotridine, the alpha- and beta-epoxides of monocrotaline, 7-angelyl-1-methylenepyrrolizidine and the methiodides of monocrotaline and senecionine. The following compounds are readily converted by rat liver microsomes in vitro into dehydroheliotridine (or dehydroretronecine): 7- and 9-angelyheliotridine, 7- and 9-angelylretronecine, 7,9-dipivalylheliotridine and otosenine. 7,9-Divalerylheliotridine, the alpha- and beta-epoxides of monocrotaline, and retusamine yield pyrrolic metabolites more slowly. The preparation and characterisation of several alkaloid derivatives are described. Chronic lung lesions were produced by most compounds which gave chronic liver lesions, although a higher dose was required in some instances. This requirement may sometimes mean that chronic lung lesions cannot be induced because of the intervention of acute or peracute deaths. Apart from this factor, structure activity requirements for pneumotoxicity are the same as for hepatotoxicity, consistent with their being both caused by the same toxic metabolites.